Study finds link between post-COVID loss of smell or taste and memory problems

Studies conducted before the COVID-19 pandemic showed that loss of smell could be an early sign of the impending onset of Alzheimer’s disease. There is evidence in the scientific literature that this sensory disorder may appear years before the first cognitive symptoms, suggesting a link between the brain regions responsible for memory and for interpreting olfactory stimuli.

This hypothesis has recently been strengthened by a study reported in European Archives of Psychiatry and Clinical Neuroscience. A group of Brazilian researchers analyzed clinical data from 701 patients treated for moderate or severe COVID-19 at Hospital das Clínicas, the hospital complex run by the University of São Paulo's Medical School (FM-USP) in São Paulo City, Brazil, between March and August 2020. 

Assessments carried out six months after their discharge from hospital showed that the patients with the most severe post-COVID smell and taste disorders performed worst in cognitive tests, especially when these involved memory, and that test results did not correlate with the severity of their condition in the acute stage of the disease. 

“Smell is an important link to the outside world and is closely related to past experiences. The smell of cake may evoke memories of a grandmother, for example. In terms of brain connections, smell interacts much more robustly with memory than with sight and hearing,” said ear, nose and throat specialist Fábio Pinna, last author of the article reporting the study.

The average hospital stay for the entire group of patients studied was 17.6 days. Their average age was 55.3. Just over half (52.4%) were male. A slightly larger proportion (56.4%) required intensive care for complications of the disease, and a little more than a third (37.4%) were intubated.

Smell and taste were assessed six months after hospital discharge by means of questionnaires that had been previously standardized for this type of study and also covered aspects relating to quality of life.

A moderate or severe gustatory deficit (reduced sense of taste) was the most frequently reported sensory complication (20%), followed by a moderate or severe olfactory deficit (18%), a moderate or severe deficit of both smell and taste (11%), and parosmia (9%) - distortion of olfactory perception, so that a previously enjoyed smell becomes unpleasant, for example. 

Olfactory hallucinations (perceiving smells of which others were unaware) were reported by 12 of the participants, and gustatory hallucinations (perceiving tastes without eating anything) by nine. In both cases, most said the hallucinations occurred only post-COVID. In response to a question about their overall state of health, 10.1% chose poor or very poor, 38.5% opted for average, and 51.4% preferred good or very good.

Psychiatric symptoms such as anxiety and depression were investigated, also using standardized questionnaires, and neuropsychological tests were applied to measure cognitive functions such as memory, attention and speed of reasoning.
Finally, statistical techniques were used to analyze all the results with the aim of detecting correlations between neuropsychiatric symptoms and sensory dysfunctions. 

Subjects reporting parosmia were found to have more memory problems more than the rest, while those with a moderate or severe gustatory deficit performed significantly worse in a test used to assess episodic memory and attention. Subjects who reported moderate or severe loss of both smell and taste were also found to have significantly impaired episodic memory. 

“We didn't find any psychiatric symptoms [such as anxiety or depression] to be associated with loss of smell and taste, but as expected we observed that attention and episodic memory were more impaired in patients with more chemosensory alterations,” said Rodolfo Damiano, first author of the article, Damiano is a PhD candidate at FM-USP with a scholarship from FAPESP. “This finding corroborates the hypothesis that COVID affects cognition, and that damage in this area doesn’t only have psychosocial or environmental causes.”

Further research

In the case of Alzheimer’s, scientists believe loss of smell may be one of the first consequences of the degenerative process that leads to a gradual loss of neurons. COVID-related loss of smell, according to Pinna, derives from the inflammation triggered by SARS-CoV-2 in the olfactory mucosa. “This inflammation reduces the amount of olfactory mucus,” he said. “We haven’t seen direct damage to olfactory neurons. They eventually degenerate, but this seems to be a secondary consequence of the loss of olfactory mucus. The mucosa atrophies and can lose the capacity to capture smells.”

The cognitive losses observed in Alzheimer’s and post-COVID syndromes derive from different pathogenic processes, but these may overlap, explained psychogeriatrician Orestes Forlenza, a professor in FM-USP's Psychiatry Department and one of the leaders of the study. “This is particularly the case in older people who already have primary cognitive symptoms and contract COVID. There is preliminary evidence that this overlapping of pathogenic factors may accelerate or intensify the progression of cognitive losses,” he said.

However, the exact mechanism leading to cognitive damage in COVID patients is unknown. The FM-USP research group plans to apply new tests to patients with loss of smell and taste in order to try to identify the brain pathways that are altered in the acute stage of the disease. Volunteers will be asked to perform tasks while undergoing a high-resolution MRI scan (7 tesla, compared with 3T usually).

“Our hypothesis is that the virus causes neuroinflammation, which leads to cognitive impairment. We don’t yet know if the damage is permanent. We'll continue to follow the patients to see if these complications clear up,” Damiano said.

The group is also investigating whether the correlation between sensory and cognitive losses occurs in people who contract COVID-19 after being vaccinated. “This involves a study similar to the one reported in the article, but taking into account the differences between vaccinated and non-vaccinated subjects, as well as the number of shots they had before being infected. The point is to find out if vaccines afford protection from neuropsychiatric complications, and whether one type of vaccine does so more than another, making it better suited to people with psychiatric diseases,” Damiano explained.

Watching for loss of smell 

According to the researchers, one of the most important messages of the article is that health workers and people in general should watch for signs of olfactory dysfunction.

“When older people start losing their sense of smell, it could be an early sign of dementia,” Damiano said. “They should see a physician for an assessment. People who notice moderate or severe loss of smell after having COVID, as well as their close relatives, should watch for signs of memory loss in the next few years.”

Pinna hopes the findings encourage physicians and patients with olfactory dysfunction to invest in treatment. “Before COVID, this problem was ignored, and treatments were neglected. The belief was that little could be done. Now, however, we have evidence that it’s important to treat chemosensory impairment in order to minimize both the loss of quality of life it causes and to prevent the development of other health problems associated with it. We have the incentive not to give up the possibility of treatment,” he said.

About São Paulo Research Foundation (FAPESP)

The São Paulo Research Foundation (FAPESP) is a public institution with the mission of supporting scientific research in all fields of knowledge by awarding scholarships, fellowships and grants to investigators linked with higher education and research institutions in the State of São Paulo, Brazil. FAPESP is aware that the very best research can only be done by working with the best researchers internationally. Therefore, it has established partnerships with funding agencies, higher education, private companies, and research organizations in other countries known for the quality of their research and has been encouraging scientists funded by its grants to further develop their international collaboration. You can learn more about FAPESP at www.fapesp.br/en and visit FAPESP news agency at www.agencia.fapesp.br/en to keep updated with the latest scientific breakthroughs FAPESP helps achieve through its many programs, awards and research centers. You may also subscribe to FAPESP news agency at http://agencia.fapesp.br/subscribe